Effect of Apolipoprotein E4 on the Driving Behavior of Patients with Amnestic Mild Cognitive Impairment or Mild Alzheimer's Disease Dementia.

BACKGROUND: The driving behavior of patients with mild Alzheimer's disease dementia (ADD) and patients with mild cognitive impairment (MCI) is frequently characterized by errors. A genetic factor affecting cognition is apolipoprotein E4 (APOE4), with carriers of APOE4 showing greater episodic memory impairment than non-carriers. However, differences in the driving performance of the two groups have not been investigated. OBJECTIVE: To compare driving performance in APOE4 carriers and matched non-carriers. METHODS: Fourteen APOE4 carriers and 14 non-carriers with amnestic MCI or mild ADD underwent detailed medical and neuropsychological assessment and participated in a driving simulation experiment, involving driving in moderate and high traffic volume in a rural environment. Driving measures were speed, lateral position, headway distance and their SDs, and reaction time. APOE was genotyped through plasma samples. RESULTS: Mixed two-way ANOVAs examining traffic volume and APOE4 status showed a significant effect of traffic volume on all driving variables, but a significant effect of APOE4 on speed variability only. APOE4 carriers were less variable in their speed than non-carriers; this remained significant after a Bonferroni correction. To further examine variability in the driving performance, coefficients of variation (COV) were computed. Larger headway distance COV and smaller lateral position COV were observed in high compared to moderate traffic. APOE4 carriers had smaller speed COV compared to non-carriers. CONCLUSION: The lower speed variability of APOE4 carriers in the absence of neuropsychological test differences indicates reduced speed adaptations, possibly as a compensatory strategy. Simulated driving may be a sensitive method for detecting performance differences in the absence of cognitive differences.

APOE e4-genotype and lifestyle interaction on cognitive performance: Results of the LIFE-Adult-study.

OBJECTIVE: Previous studies have shown that the e4-allele of the APOE gene is associated with a higher risk of developing dementia. Our study investigated whether well-known associations between lifestyle factors and cognitive functioning may be stronger in individuals who carry the dementia risk variant of the APOE gene and whether this association is amplified with older age. METHOD: Data analysis comprised 7,526 participants (aged 40- to 79-years-old) from the population-based LIFE-Adult-study. The effect of the APOE e4-allele on the association between lifestyle factors (smoking, physical activity, being overweight, occupational attainment) and cognitive performance (trail making test [TMT] B, verbal fluency test [VFT]) was analyzed via multivariate generalized linear modeling adjusted for APOE e2-allele, age, gender, education, stroke, and heart attack. RESULTS: Smoking, less physical activity, and lower occupational attainment was associated with a poorer performance in the TMT B and VFT. Neither the APOE e4-allele nor interactions with the APOE e4-allele were significantly associated with cognitive performance. The association between physical activity and occupational attainment on performance in the TMT B were stronger in older age, but the APOE gene did not modify those associations. CONCLUSIONS: Our findings suggest that the dementia risk variant of the APOE gene does not alter the association between lifestyle factors and cognitive performance in the general population aged 40- to 79-years-old. However, as lifestyle factors impact cognitive aging, research efforts should focus on establishing effective interventions promoting healthy lifestyle behaviors to counteract adverse cognitive aging processes. (PsycINFO Database Record

Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins. METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo. RESULTS: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats. INTERPRETATION: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222.

Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial.

IMPORTANCE: Sporadic Alzheimer disease (AD) is caused in part by decreased clearance of the ß-amyloid (Aß) peptide breakdown products. Lipid-depleted (LD) apolipoproteins are less effective at binding and clearing Aß, and LD Aß peptides are more toxic to neurons. However, not much is known about the lipid states of these proteins in human cerebrospinal fluid. OBJECTIVE: To characterize the lipidation states of Aß peptides and apolipoprotein E in the cerebrospinal fluid in adults with respect to cognitive diagnosis and APOE ε4 allele carrier status and after a dietary intervention. DESIGN: Randomized clinical trial. SETTING: Veterans Affairs Medical Center clinical research unit. PARTICIPANTS: Twenty older adults with normal cognition (mean [SD] age, 69 [7] years) and 27 with amnestic mild cognitive impairment (67 [6] years). INTERVENTIONS: Randomization to a diet high in saturated fat content and with a high glycemic index (High diet; 45% of energy from fat [>25% saturated fat], 35%-40% from carbohydrates with a mean glycemic index >70, and 15%-20% from protein) or a diet low in saturated fat content and with a low glycemic index (Low diet; 25% of energy from fat [<7% saturated fat], 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein). MAIN OUTCOMES AND MEASURES: Lipid-depleted Aß42 and Aß40 and apolipoprotein E in cerebrospinal fluid. RESULTS: Baseline levels of LD Aß were greater for adults with mild cognitive impairment compared with adults with normal cognition (LD Aß42, P = .05; LD Aß40, P = .01). These findings were magnified in adults with mild cognitive impairment and the ε4 allele, who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis (P < .001). The Low diet tended to decrease LD Aß levels, whereas the High diet increased these fractions (LD Aß42, P = .01; LD Aß40, P = .15). Changes in LD Aß levels with the Low diet negatively correlated with changes in cerebrospinal fluid levels of insulin (LD Aß42 and insulin, r = -0.68 [P = .01]; LD Aß40 and insulin, r = -0.78 [P = .002]). CONCLUSIONS AND RELEVANCE: The lipidation states of apolipoproteins and Aß peptides in the brain differ depending on APOE genotype and cognitive diagnosis. Concentrations can be modulated by diet. These findings may provide insight into the mechanisms through which apolipoprotein E4 and unhealthy diets impart risk for developing AD.

Enabling a multidisciplinary approach to the study of ageing and Alzheimer's disease: an update from the Australian Imaging Biomarkers and Lifestyle (AIBL) study.

The Australian Imaging Biomarkers and Lifestyle (AIBL) study is a longitudinal study of 1,112 volunteers from healthy, mild cognitive impairment (MCI) and Alzheimer's disease (AD) populations who are assessed at 18-month intervals in order to enable prospective research into ageing and AD. Using a multidisciplinary battery, AIBL assessments comprise the extensive study of clinical factors and cognitive function, collection of blood and cerebrospinal fluid (CSF) samples for biomarker discovery, structural and ß-amyloid (Aß) neuroimaging, and obtaining information on diet and physical activity patterns of the cohort. Now in its seventh year, AIBL is part of a substantial international effort to prospectively study the relationships between clinical characteristics and putative AD biomarkers in groups who carry different risk factors for AD. The identification of biomarkers would provide a window of opportunity to assess AD risk in individuals prior to the onset of advanced clinical symptoms, in addition to facilitating testing of therapeutic and lifestyle interventions likely to emerge within the next decade that prevent or delay symptom emergence in those at high risk for developing AD. In this paper, we present key findings from the AIBL study and discuss how they contribute to our understanding of AD pathogenesis and diagnosis.

Down's syndrome and Alzheimer's disease: towards secondary prevention.

A public-private partnership to establish biomarkers of dementia in Down's syndrome could aid the development of preventive therapies for the dementia associated with both Down's syndrome and Alzheimer's disease, based on the apparent common pathogenic role of amyloid precursor protein in the two conditions.

APOE epsilon4 allele carriers: Biological, psychological, and social variables associated with cognitive impairment.

OBJECTIVE: The apolipoprotein (APOE) epsilon4 allele genotype is a risk factor for dementia, but not all people with the APOE epsilon4 allele develop cognitive impairment (CI). Among participants with the APOE epsilon4 allele (N = 664), we identified biological, psychological, and social variables that discriminate between participants who develop CI from those who do not. We then determined if these variables predicted CI in noncarriers (N = 1421). In the sample as a whole we then determined if each of these identified variables moderate the relationship between the APOE epsilon4 allele and CI. METHODS: We used data from a biracial community-dwelling sample of older adults. Data were collected at four time points over a 10-year period. Cognitive functioning was assessed at each wave, using the Short Portable Mental Status Questionnaire (SPMSQ). APOE genotyping was performed at Wave 3. RESULTS: Among APOE epsilon4 allele carriers, but not noncarriers, variables associated with CI included white race, female gender, low BMI, number of negative life events, and health problems (high blood pressure, heart disease, and stroke). In analyses testing for moderate effects and including the entire sample, significant interactions with APOE epsilon4 allele and predictor variables revealed that white race, low BMI, stroke, heart disease, and negative life events had a greater effect on CI among those with the APOE epsilon4 allele compared to those without the allele. CONCLUSION: There are biological, psychological, and social variables associated with increased risk for CI among individuals with the APOE epsilon4 allele.

Problems meeting basic needs moderate the association between the APOE epsilon4 allele and cognitive decline.

OBJECTIVES: The ApolipoproteinE epsilon4 (APOE epsilon4) allele influences cognitive decline (CD) in some but not in all individuals. The purpose of this study was to investigate whether problems meeting basic needs (BN) (e.g., having enough money to meet needs, having enough money for emergencies, having adequate housing, and having enough heat) influences the relationship between the APOE epsilon4 allele and CD. We predicted that problems meeting BN would have a greater influence on CD among those with the APOE epsilon4 allele than those without the allele. METHODS: Participants consisted of community-dwelling older adults from the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE). Data were drawn from Waves 1 and 2, which were 3 years apart. Cognitive functioning was assessed at both waves so that change in cognitive status was examined over time, and cognitive status was controlled at baseline. Genotyping, however, was not obtained until Wave 3. RESULTS: The APOE epsilon4 allele and problems meeting BN independently predicted CD. Importantly, the influence of BN on CD was greater for individuals with the APOE epsilon4 allele compared to those without the allele. Other indicators of socioeconomic status (e.g., education, income) did not interact with the APOE epsilon4 allele in predicting CD. CONCLUSIONS: There is a synergistic effect of perceived problems meeting BN and the APOE epsilon4 allele on jointly influencing cognitive functioning. Although genetic risk factors are not easily modifiable, resource deprivation may be more amenable to interventions, which may reduce risk for CD.

Depressive symptoms moderate the influence of the apolipoproteine epsilon4 allele on cognitive decline in a sample of community dwelling older adults.

OBJECTIVES: The apolipoproteinE epsilon4 (APOE epsilon4) allele and a history of depression are each separate risk factors for cognitive decline (CD). However, little research has investigated whether a history of depression influences the relationship between APOE epsilon4 and CD. The present study examined whether depressive symptoms had greater influence on subsequent CD among participants with APOE epsilon4 than those without the allele. DESIGN: Prospective 6-year longitudinal study. SETTING: Community in-home interviews. PARTICIPANTS: A biracial sample of community dwelling older adults (N = 1,992) from the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE). MEASUREMENTS: Data were drawn from Waves 1 to 3 of the EPESE, which were conducted 6 years apart. Cognitive functioning and depressive symptoms were assessed at both waves, and APOE genotyping was completed during the Wave 3 assessment. RESULTS: Regression analyses revealed that depressive symptoms and the APOE epsilon4 allele independently predicted CD. Importantly, the influence of depressive symptoms on CD was greater for individuals with the APOE epsilon4 allele compared with those without the allele. CONCLUSION: Depressive symptoms and the APOE epsilon4 allele are independent contributors to CD. Moreover, the influence of depressive symptoms on CD is greater among individuals with the APOE epsilon4 allele. Depression and the APOE epsilon4 allele may act together in disrupting neurological functioning, which may in turn lower an individual's cognitive reserve capacity. Given the efficacious treatments currently available for depression, future research should investigate the extent to which interventions for depression may reduce the risk for subsequent CD.

Estimating interaction between genetic and environmental risk factors: efficiency of sampling designs within a cohort.

Large prospective cohorts originally assembled to study environmental risk factors are increasingly exploited to study gene-environment interactions. Given the cost of genetic studies in large samples, being able to select a subsample for genotyping that contains most of the information from the cohort would lead to substantial savings. We consider nested case-control and case-cohort sampling designs with and without stratification and compare their efficiency relative to the entire cohort for estimating the effects of genetic and environmental risk factors and their interactions. Asymptotic calculations show that the relative efficiency of the case-cohort and nested case-control designs implementing the same sampling stratification are similar over a range of scenarios for the relationships among genes, environmental exposures, and disease status. Sampling equal numbers of exposed and unexposed subjects improves efficiency when the exposure is rare. The case-cohort designs had a slight advantage in simulations of sampling designs within the Framingham Offspring Study, using the interaction between apolipoprotein E and smoking on the risk of coronary heart disease as an example. It was possible to estimate the interaction effect with precision close to that of the full cohort when using case-cohort or nested case-control samples containing fewer than half the subjects of the cohort.